Common susceptibility loci for male breast cancer

Sarah Maguire 1 2, Eleni Perraki 2, Katarzyna Tomczyk 2, Michael E Jones 3, Olivia Fletcher 2, Matthew Pugh 2, Timothy Winter 1, Kyle Thompson 1, Rosie Cooke 3, kConFab Consortium; Alison Trainer 4, Paul James 5 6, Stig Bojesen 7 8 9, Henrik Flyger 10, Heli Nevanlinna 11, Johanna Mattson 12, Eitan Friedman 13 14, Yael Laitman 13 14, Domenico Palli 15, Giovanna Masala 15, Ines Zanna 15, Laura Ottini 16, Valentina Silvestri 16, Antoinette Hollestelle 17, Maartje J Hooning 17, Srdjan Novaković 18, Mateja Krajc 19, Manuela Gago-Dominguez 20 21, Jose Esteban Castelao 22, Hakan Olsson 23, Ingrid Hedenfalk 23, Emmanouil Saloustros 24, Vasilios Georgoulias 25, Douglas F Easton 26 27, Paul Pharoah 26 27, Alison M Dunning 27, D Timothy Bishop 28, Susan L Neuhausen 29, Linda Steele 29, Alan Ashworth 30, Montserrat Garcia Closas 31, Richard Houlston 3, Anthony Swerdlow 3 32, Nick Orr 1 2

Affiliations

PMID: 32785646
DOI: 10.1093/jnci/djaa101

Abstract

Background: The aetiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.

Methods: We performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score (PRS) and MBC. All statistical tests were two-sided.

Results: The GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10-30).

Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.